In the previous years the research supported by this grant has dealt primarily with the mechanisms of metabolism of the phosphorothionate insecticides. In the current renewal of this application the focus of the proposed research has been expanded to include a number of other compounds containing the thiono-sulfur group. The major objectives of these studies are to attempt to determine: (1) the route of metabolism of the thiono-sulfur moiety in various chemical groups such as a thioamide, thioureas, thiouracils, thioimidazole, phosphorothionates and carbon disulfide; (2) the ability of these various thiono-sulfur containing compounds to produce liver damage; (3) the ability of these thiono-sulfur containing compounds to decrease the level of hepatic cytochrome P-450 and inhibit monooxygenase activity when administered in vivo or incubated with hepatic microsomes in vitro; (4) the nature of the covalent bond(s) formed between the sulfur atom released in the metabolism of some of these compounds and the amino acids of cytochrome P-450; (5) the structure of the products formed in the covalent binding of the carbon and phosphorus-containing portions of $ parathion and the carbon containing portions of carbon disulfide and thioacetamide to the proteins of hepatic microsomes; (6) the mechanism by which the metabolism of thiono-sulfur containing compounds leads to inhibition of the cytochrome P-450 containing monooxygenases and liver necrosis.